Acodrug consists of two drugmoieties, generally "active against the same disease", that are joined through one or morecovalent chemical bonds to create a singlenew chemical entity;[1] they can also be described as amutualprodrug, recognising that acatabolicbiosynthetic step is most often required to liberate the two drugs.[2] While acting against the same disease, the two moities may operate via differentmechanisms of action, and so display differing specific therapeutic effects.[citation needed] The recognised advantages of a codrug approach to small moleculedrug design include the possibilities of (i) combined efficacies of the two drugs that are therapeutically synergistic, (ii) altered properties that improve the pharmacokinetics (e.g., halflife) of the codrug over its individually administered components (iii) improved modes ofdrug delivery, and (iv) masking of reactive functional groups of each component drug, possibly improving shelf life (as well as pharmacokinetics).[1][2]
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An effective codrug should be pharmacologically inactive in its own right but should release the constituent drugs upon biochemical breakage of the chemical linkage at the target tissue where their therapeutic effects are needed. As such, the chemical linkage (usually acovalent bond) should be subjectable to biodegradation, such as hydrolysis, by an enzymatic or non-enzymatic mechanism. The differential distribution of enzymes capable of catalyzing the breakage of the chemical linkage in different tissues may be exploited to achieve tissue-specific metabolism of the codrug to release the constituent drugs.
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